We two alone will sing: the two-substrate alpha-keto acid-dependent oxygenases.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are the only two known members of the alpha-keto acid-dependent oxygenases that adopt the fold common to the vicinal oxygen chelate superfamily of enzymes. All other oxygenases of this type have a jellyroll fold. Despite a clearly different ancestry, the salient details of HPPD and HMS catalysis are the same as all alpha-keto acid-dependent oxygenases. All alpha-keto acid-dependent oxygenases use reducing equivalents from an alpha-keto acid to reduce dioxygen via an active site ferrous ion mediator and then catalyze decarboxylation of the alpha-keto acid to promote the formation of a high valence iron-oxo species. The most common purpose of which is to then hydroxylate the substrate. This mini-review summarizes the structural and mechanistic data assembled in recent years for HPPD and HMS in the context of both their roles in nature and the vicinal oxygen chelate and alpha-keto acid-dependent oxygenases superfamilies.